This invention relates to indole and azaindole derivatives and their use as tachykinin antagonists, and in particular as neurokinin-1 receptor antagonists.
We have now found a class of indole and azaindole derivatives which are potent receptor antagonists of tachykinins, especially of the neurokinin-1 (substance P) receptor.
The present invention accordingly provides the compounds of the formula (I): 
wherein:
Het represents a heterocyclic residue selected from: 
where the dotted line in (b) represents an optional double bond;
A completes a fused pyridine ring;
B completes a fused benzene or pyridine ring;
X represents an oxygen atom, a sulfur atom, two hydrogen atoms, xe2x95x90NH or xe2x95x90N(C1-6alkyl);
Y is a straight or branched C1-4alkylene chain optionally substituted by halogen, oxo or hydroxy; or Y represents a straight or branched C2-4alkenylene or C2-4alkynylene chain;
Z represents CR5R6 or NR7 so as to complete a piperidine or piperazine ring;
R1a and R1b each independently represent hydrogen, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, halogen, cyano, NRaRb, SRa, SORa, SO2Ra, OSO2Ra, NRaCORb, CORa, CO2Ra or CONRaRb;
R2 represents hydrogen, C1-6alkyl, fluoroC1-6alkyl, (CH2)mCORa, (CH2)pCO2Ra, (CH2)pOH, (CH2)mCONRaRb, (CH2)mphenyl or SO2C1-6alkyl;
R3 represents phenyl, biphenyl, naphthyl or heteroaryl, wherein said phenyl, biphenyl, naphthyl or heteroaryl group may be optionally substituted by one, two or three groups independently selected from halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, NO2, cyano, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl, C1-4alkoxyC1-4alkyl or xe2x80x94O(CH2)1-2Oxe2x80x94;
R4 represents hydrogen, C1-6alkyl, carbonyl (xe2x95x90O), (Ch2)pphenyl or a C1-2alkylene bridge across the piperidine or piperazine ring;
R5 and R6 each independently represent hydrogen, halogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C2-6alkenyl, cyano, naphthyl, fluorenyl, (CH2)mphenyl, (CH2)mheteroaryl, CH(phenyl)2, CH(C1-6alkyl)(phenyl), C(C1-6alkyl)(phenyl)2, CO(phenyl), C(OH)(phenyl)2, C2-4alkenyl(phenyl), (CH2)mNRcRd, (CH2)pCONRcRd, (CH2)pNRaCORb, (CH2)mCORc, (CH2)mCO2Rc or (CH2)mOH wherein said phenyl, naphthyl, fluorenyl or heteroaryl groups may be optionally substituted by one, two or three groups independently selected from halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, NO2, cyano, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl, C1-4alkoxyC1-4alkyl or xe2x80x94O(CH2)1-2Oxe2x80x94; or R5 and R6 together are linked so as to form a 5- or 6-membered ring optionally substituted by xe2x95x90O, xe2x95x90S or a C1-4alkyl or hydroxy group, and optionally containing a double bond, which ring may optionally contain in the ring one or two heteroatoms selected from O and S, or groups selected from NRc, SO or SO2, and to which ring there is either fused or attached a benzene or thiophene ring, which benzene or thiophene ring is optionally substituted by 1, 2 or 3 substituents selected from C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenylC1-4alkyl, trifluoromethyl, cyano, ORa, SRa, SORa, SO2Ra, NRaRb, NRaCORb, NRaCO2Rb, NRaSO2Rb, CORa, CO2Ra or CONRaRb, wherein the phenyl moiety of a phenylC1-4alkyl group may be substituted by C1-6alkyl, C1-6alkoxy, halogen or trifluoromethyl;
R7 represents C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C2-6alkenyl, (CH2)mphenyl, naphthyl, fluorenyl, (CH2)mheteroaryl, CH(phenyl)2, CH(C1-6alkyl)(phenyl), C2-4alkenyl(phenyl), (CH2)pNRcRd, (CH2)mCONRcRd, (CH2)mCORc, (CH2)mCO2Rc or (CH2)pOH, where said phenyl, naphthyl, fluorenyl or heteroaryl groups may be optionally substituted by one, two or three groups independently selected from halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, NO2, cyano, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl, C1-4alkoxyC1-4alkyl or xe2x80x94O(CH2)1-2Oxe2x80x94;
Ra and Rb each independently represents hydrogen, C1-4alkyl, fluoroC1-4alkyl or phenyl; or the group xe2x80x94NRaRb may form a 5- or 6-membered ring optionally substituted by xe2x95x90O, xe2x95x90S or a C1-4alkyl or hydroxy group, and optionally containing a double bond, which ring may optionally contain in the ring one or two heteroatoms selected from O and S, or groups selected from NRc, SO or SO2;
Rc and Rd each independently represents hydrogen, C1-4alkyl, fluoroC1-4alkyl, C2-4alkenyl, CORa, SO2Ra, phenyl or benzyl or Rc and Rd, together with the nitrogen atom to which they are attached, form a heteroaliphatic ring of 4 to 7 atoms, to which ring there may optionally be fused a benzene ring;
m is zero or an integer from 1 to 4;
p is an integer from 1 to 4;
or a pharmaceutically acceptable salt thereof.
In the heterocyclic residues (a)-(e) represented by xe2x80x9cHetxe2x80x9d, pyridine rings completed by A or B may be fused to the 5-membered rings in any of the possible orientations. Thus, for example, (a) may represent a pyrrolo[2,3-b]pyridine system, a pyrrolo[2,3-C]pyridine system, a pyrrolo[3,2-c]pyridine system, or a pyrrolo[3,2-b]pyridine system.
In a subgroup of the compounds of formula I, B completes a fused benzene ring.
In another subgroup of the compounds of formula I, when Het represents (b), a double bond is present in the position indicated by the dotted line.
A preferred group of compounds of formula I is that wherein R1a and R1b each independently represent hydrogen, halogen, C1-6alkyl, C2-6alkenyl, fluoroC1-6alkoxy, NRaRb, CORa, CO2Ra, or heteroaryl. When R1a and R1b are both other than hydrogen, preferably R1a and R1b are the same. When R1a is other than hydrogen and R1b is hydrogen, R1a is preferably attached to the 5-position when Het represents (a) or (e), to the 5- or 6-position when Het represents (b) or (d), and to the 6-position when Het represents (c).
A particularly preferred group of compounds of formula (I) is that wherein R1a and R1b each independently represent hydrogen, methyl, vinyl, trifluoromethoxy, fluorine, chlorine, bromine, pyrrolidinyl, piperidinyl, morpholino, acetyl, methoxycarbonyl, pyridyl (especially 3-pyridyl) or furyl (especially 2-furyl).
An especially preferred group of compounds of formula (I) is that wherein R1a represents methyl or chloro, and R1b is hydrogen.
A subclass of compounds of formula (I) is that wherein Het represents (a) or (e). Within this subclass, a preferred group of compounds is that wherein R2 represents hydrogen, C1-6alkyl, fluoroC1-6alkyl, (CH2)mCORa, (CH2)pCORa, (CH2)pOH or (CH2)mphenyl. More preferably, R2 represents C1-3alkyl (especially methyl, ethyl or isopropyl), fluoroC1-3alkyl (especially trifluoromethyl or 2,2,2-trifluoroethyl), COCH3, CH2CO2H, CH2CO2CH3, (CH2)1-2OH (especially CH2CH2OH) or benzyl. An especially preferred group of compounds within this subclass is that wherein R2 is hydrogen or methyl.
Another preferred group of compounds of formula (I) is that wherein R3 represents phenyl, biphenyl, naphthyl (especially 2-naphthyl) or heteroaryl (especially 2- or 3-pyridyl) wherein said phenyl, biphenyl, naphthyl or heteroaryl group is optionally substituted by one or two groups selected from halogen, C1-6alkyl, C1-6alkoxy, trifluoroC1-6alkyl, fluoroC1-6alkoxy or C2-6alkenyl.
A particularly preferred class of compounds of formula (I) is that wherein R3 represents phenyl, biphenyl, naphthyl (especially 2-naphthyl) or heteroaryl (especially 2- or 3-pyridyl) wherein said phenyl, biphenyl, naphthyl or heteroaryl group is optionally substituted by one or two groups selected from fluorine, chlorine, bromine, C1-4alkyl (especially methyl, isopropyl or tertiary butyl), methoxy, trifluoromethyl, trifluoromethoxy or vinyl.
An especially preferred group of compounds of formula (I) is that wherein R3 represents 2-pyridyl, 3-pyridyl or phenyl optionally substituted by one or two groups selected from fluorine, chlorine, bromine, C1-4alkyl (especially methyl, isopropyl or tertiary butyl), methoxy, trifluoromethyl, trifluoromethoxy or vinyl.
A most especially preferred class of compounds of formula (I) is that wherein R3 represents phenyl, 4-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 2-pyridyl or 3-pyridyl.
A further preferred group of compounds of formula (I) is that wherein R4 represents hydrogen, methyl, carbonyl, benzyl or a methylene bridge across the 2,5-positions on the piperidine or piperazine ring.
As especially preferred group of compounds of formula (I) is that wherein R4 is hydrogen.
In a subclass of the compounds of formula (I), Z represents CR5R6. Within this subclass, a preferred group of compounds is that wherein R5 represents halogen, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenyl, heteroaryl, (CH2)pphenyl, (CH2)pheteroaryl, CH(phenyl)2, CH(C1-6alkyl)(phenyl), C(C1-6alkyl)(phenyl)2, CO(phenyl), C(OH)(phenyl)2, or (CH2)pNRcRd, wherein said phenyl or heteroaryl group is optionally substituted by one or two substituents selected from halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, NO2, cyano, SRa or xe2x80x94O(CH2)1-2Oxe2x80x94.
A particularly preferred group of compounds in this subclass is that wherein R5 represents C5-7cycloalkyl (especially cyclohexyl), phenyl, heteroaryl, (CH2)pphenyl (especially wherein p is 1 or 2), CO(p-methoxyphenyl), C(OH)(phenyl)2, or (CH2)pNRcRd (especially where Rc and Rd each independently represent hydrogen, C1-4alkyl, C2-4alkenyl, CORa (especially wherein Ra is methyl or ethyl), SO2Ra (especially wherein Ra is methyl), phenyl or benzyl, or Rc and Rd, together with the nitrogen atom to which they are attached, form a piperidine ring; and especially wherein p is zero or 1), wherein each of said phenyl or heteroaryl groups may be substituted by one or two groups independently selected from halogen, C1-4alkyl, C1-4alkoxy, fluoroC1-4alkyl, fluoroC1-4alkoxy, NO2, cyano and SO2Ra (especially wherein Ra represents C1-4alkyl), or said phenyl or heteroaryl group may be substituted by the group xe2x80x94O(CH2)1-2Oxe2x80x94. Particularly preferred are compounds in which said phenyl groups are unsubstituted or substituted by one or two substituents independently selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, nitro, cyano and thiomethyl, or said phenyl is substituted by xe2x80x94OCH2Oxe2x80x94. Also preferred are compounds in which said heteroaryl groups are unsubstituted or are monosubstituted by methyl or trifluoromethyl.
Another preferred group of compounds within this subclass is that wherein R6 represents hydrogen, fluorine, cyano, (CH2)mNRcRd, (CH2)pNRaCORb, (CH2)mCO2Rc or (CH2)mOH, where Ra, Rb, Rc and Rd are as previously defined.
Particularly preferred are compounds wherein R6 represents hydrogen, cyano, NRcRd (especially wherein Rc and Rd are both C1-3alkyl, most especially methyl), CH2NHCORb (especially wherein Rb is C1-3alkyl, most especially methyl), CO2Rc (especially wherein Rc is hydrogen or C1-3alkyl, most especially hydrogen or methyl), or (CH2)mOH (especially where m is zero or 1).
Very aptly, R5 represents benzyl and R6 represents OH.
Where R5 and R6 are taken together there is preferably formed a 5- or 6-membered ring optionally substituted by xe2x95x90O or a hydroxy group, and optionally containing a double bond, which ring optionally contains in the ring an oxygen or sulfur atom or 1 or 2 NH groups, and to which ring is either fused or attached a benzene ring, which benzene ring is optionally substituted by C1-3alkyl or SO2Ra, where Ra is as previously defined.
In particular, when R5 and R6 are so linked as to form a 5- or 6-membered ring, suitable definitions of the CR5R6 moiety are selected from: 

Particularly preferred examples of the CR5R6 moiety are selected from: 
In a further subclass of the compounds of formula (I), Z represents NR7. Within this subclass, a preferred group of compounds is that wherein R7represents C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C2-6alkenyl, naphthyl, fluorenyl, (CH2)mphenyl, (CH2)mheteroaryl, CH(phenyl)2, CH(C1-6alkyl)(phenyl), C2-4alkenyl(phenyl), (CH2)pNRcRd, (CH2)pCONRcRd, (CH2)mCORc or (CH2)mCO2Rc wherein said phenyl or heteroaryl group is optionally substituted by one or two substituents selected from halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, NO2, cyano, SRa or xe2x80x94O(CH2)1-2Oxe2x80x94.
A particularly preferred group of compounds within this subclass is that wherein R7represents C3-6alkyl (especially propyl, isopropyl or isopentyl), C5-7cycloalkyl (especially cyclohexyl), C3-7cycloalkylC1-2alkyl (especially cyclopropylmethyl, cyclohexylmethyl or 2-cyclohexylethyl), C2-4alkenyl (especially vinyl), naphthyl (especially 1-naphthyl), fluorenyl (especially 9-fluorenyl), (CH2)mphenyl (especially wherein m is 0, 1 or 2), (CH2)mheteroaryl (especially wherein m is 0 or 1), CH(phenyl)2, CH(C1-2alkyl)(phenyl), C2-4alkenyl(phenyl) (especially CH2xe2x80x94CHxe2x95x90CH phenyl), (CH2)pNRcRd (especially where Rc and Rd each represent C2-4alkenyl; and especially wherein p is 2), (CH2)pCONRcRd (especially wherein Rc and Rd each independently represent hydrogen, C1-4alkyl, C2-4alkenyl, phenyl or benzyl or Rc and Rd, together with the nitrogen atom to which they are attached, form a heteroaliphatic ring of 5 or 6 atoms to which ring there is fused a benzene ring; and especially wherein p is 1), (CH2)mCORc (especially wherein Rc represents phenyl; and especially wherein m is zero) or (CH2)mCO2Rc (especially wherein Rc represents hydrogen or C1-4alkyl; and especially wherein m is zero or 1), wherein said phenyl or heteroaryl groups may be substituted by one or two groups independently selected from halogen, C1-4alkyl, C1-4alkoxy, fluoroC1-4alkyl, fluoroC1-4alkoxy, NO2, cyano and SRa (especially wherein Ra represents C1-4alkyl), or said phenyl or heteroaryl group may be substituted by the group xe2x80x94O(CH2)1-2Oxe2x80x94. Particularly preferred are compounds in which said phenyl groups are unsubstituted or substituted by one or two substituents independently selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, nitro, cyano and thiomethyl, or said phenyl is substituted by xe2x80x94OCH2Oxe2x80x94. Also preferred are compounds in which said heteroaryl groups are unsubstituted or are monosubstituted by methyl or trifluoromethyl.
R7 very aptly represents 2-methoxyphenyl.
Another preferred group of compounds of formula (I) is that wherein X represents an oxygen atom, two hydrogen atoms, or xe2x95x90NH. Most especially preferred are compounds wherein X is an oxygen atom.
A further preferred group of compounds of formula (I) is that wherein Y is xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH(CH3)xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, and most especially xe2x80x94CH2CH2xe2x80x94.
Another preferred group of compounds of formula (I) is that wherein X is two hydrogen atoms and Y is xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2C(O)xe2x80x94, xe2x80x94CH2CHOHxe2x80x94 or xe2x80x94CH2CHFxe2x80x94.
As used herein, NRcRd is preferably NH2, NHCH3 or N(CH3)2; NRaCORb is preferably NHCOCH3, N(CH3)COCH3 or N(Ph)COCH3; NRaCO2Rb is preferably NHCO2CH3 or N(CH3)CO2CH3; NRaSO2Rb is preferably NHSO2CH3, N(CH3)SO2CH3 or N(Ph)SO2CH3; and CO2Ra is preferably CO2H, CO2CH3 or CO2CH2CH3.
When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term xe2x80x9calkylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d as a group or part of a group encompasses both straight and branched embodiments. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
As used herein, the terms xe2x80x9cfluoroC1-6alkylxe2x80x9d and fluoroC1-6alkoxy means a C1-6alkyl or C1-6alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Similarly, the term xe2x80x9cfluoroC1-4alkylxe2x80x9d means a C1-4alkyl group in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroC1-3alkyl and fluoroC1-3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCH2CF3.
The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.
Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
As used herein, the terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.
As used herein, the term xe2x80x9cheteroarylxe2x80x9d as a group or part of a group means a heteroaromatic ring selected from pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indolyl, benzofuranyl, benzthiophenyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl or benzisothiazolyl. Particularly preferred examples of xe2x80x9cheteroarylxe2x80x9d groups include pyridyl, indolyl and triazolyl, especially 2-pyridyl, 3-pyridyl, 2-indolyl and 1,2,4-triazol-3-yl.
When used herein the term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
A particularly preferred subset of the compounds of formula (I) are in accordance with formula (Ia): 
wherein Het1 represents a residue selected from: 
Z1 represents CR15R16 or NR17;
R11 represents hydrogen, chlorine or methyl, and when Het1 represents (b1) or (d1), R11 is in the 5-position or the 6-position;
R12 represents a hydrogen atom or a group selected from C1-3alkyl, fluoroC1-3alkyl, COCH3, or (CH2)2OH;
R13 represents a halogen atom or a group selected from C1-4alkyl, C2-4alkenyl, fluoroC1-4alkyl, C1-4alkoxy or fluoroC1-4alkoxy;
R15 represents cyclohexyl, phenyl, 2-indolyl, CH2phenyl, CH2CH2phenyl, CO(p-methoxyphenyl), C(OH)(phenyl)2, NRcRd or CH2NRcRd (where Rc and Rd each independently represent hydrogen, methyl, COCH3, COCH2CH3, SO2CH3 or phenyl, or Rc and Rd, together with the nitrogen atom to which they are attached, form a piperidine ring) and wherein each phenyl group is optionally substituted by one or two substituents selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethoxy or SO2CH3;
R16 represents hydrogen, fluorine, cyano, NRcRd (where Rc and Rd each independently represent hydrogen or methyl), NHCOCH3, CH2NHCOCH3, CO2H, CO2CH3, OH or CH2OH;
or R15 and R16 together are so linked as to form a 5- or 6-membered ring optionally substituted by xe2x95x90O, and optionally containing a double bond, which ring optionally contains in the ring an oxygen or sulfur atom or 1 or 2 NH groups, and to which ring is either fused or attached a benzene ring, which benzene ring is optionally substituted by methyl or SO2CH3;
R17represents a group selected from C3-6alkyl, C5-7cycloalkyl, C3-7cycloalkylC1-2alkyl, phenyl, naphthyl, benzyl, xcex1-methylbenzyl, phenylethyl, xe2x80x94CH2CON(CH3)phenyl, xe2x80x94CH2CON(CH3)benzyl, xe2x80x94CH2CONRcRd (where Rc and Rd, together with the nitrogen atom to which they are attached, form a heteroaliphatic ring of 5 or 6 atoms to which ring there is fused a benzene ring), xe2x80x94CH2CON(CH3)C2-4alkenyl, or xe2x80x94(CH2)mCO2Rc (where Rc is hydrogen or C1-4alkyl and m is zero or 1), wherein said phenyl and benzyl groups may be substituted by a group selected from halogen, C1-3alkyl, C1-3alkoxy, fluoroC1-3alkyl, fluoroC1-3alkoxy, NO2, cyano, and xe2x80x94Sxe2x80x94C1-3alkyl or said phenyl and benzyl groups may be substituted by the group xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94.
Particularly preferred compounds of formula (Ia) are those wherein R12 represents hydrogen, methyl, COCH3 or xe2x80x94(CH2)2OH, especially hydrogen or methyl.
Another preferred class of compounds of formula (Ia) is that wherein R13 represents chlorine, bromine, fluorine, methyl, ethyl, isopropyl, trifluoromethyl or vinyl, especially chlorine, bromine, fluorine or methyl
A further preferred class of compounds of formula (Ia) is that wherein Z1 represents CR15R16; R15 represents cyclohexyl, phenyl, benzyl, 4-chlorophenyl, 3-trifluoromethylphenyl, NH(phenyl), N(CH3)(phenyl) or N(COCH2CH3)(phenyl); and R16 represents hydrogen, fluorine, hydroxy or CO2CH3. Very aptly, R15 represents benzyl and R16 represents hydroxy.
A further preferred class of compounds of formula (Ia) is that wherein Z1 represents NR17 and R17 represents phenyl, benzyl, cyclohexyl, cyclohexylmethyl, cyclopropylmethyl, isopentyl, xe2x80x94CH2CON(CH3)phenyl, xe2x80x94CH2CON(CH3)benzyl, or xe2x80x94CH2CO2CH2CH3, wherein said phenyl and benzyl groups may be substituted by a group selected from fluorine, chlorine, methyl, methoxy, trifluoromethoxy, NO2, methylthio or by the group xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94. Very aptly, R17 represents 2-methoxyphenyl.
Examples of compounds in accordance with the invention include the following:
1-{3-[5-chloro-2-(4-chlorophenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl]-1-oxopropyl}-4-(phenylmethyl)-4-piperidinol;
1-{3-[5-chloro-2-(4-chlorophenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-3-yl]-1-oxopropyl}-4-(phenylmethyl)-4-piperidinol;
1-{3-[2-(4-chlorophenyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine-3-yl]-1-oxopropyl}-4-(phenylmethyl)-4-piperidinol;
1-{3-[5-chloro-2-(4-chlorophenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-yl]-1-oxopropyl}-4-(phenylmethyl)-4-piperidinol;
1-{3-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-yl]-1-oxopropyl}-4-(phenylmethyl)-4-piperidinol;
1-{3-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine;
1-{3-[6-chloro-2-(4-fluorophenyl)-1-H-indol-1-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine;
1-{3-[5-chloro-2-(4-chlorophenyl)-1-H-indol-1-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine;
1-{3-[5-methyl-2-(4-methylphenyl)-1-H-benzimidazol-1-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine;
1-{3-[6-methyl-2-(4-methylphenyl)-1-H-benzimidazol-1-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine;
(2RS-cis)-1-{3-[5-chloro-2-(4-chlorophenyl)-2,3-dihydro-1-methyl-1-H-indol-3-yl]-1-oxopropyl}-4-(phenylmethyl)-4-piperidinol;
(2RS-trans)-1-{3-[5-chloro-2-(4-chlorophenyl)-2,3-dihydro-1-methyl-1H-indol-3-yl]-1-oxopropyl}-4-(phenylmethyl)-4-piperidinol;
(2RS-cis)-1-{3-[5-chloro-2-(4-chlorophenyl)-2,3-dihydro-1-methyl-1H-indol-3-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine; and
pharmaceutically acceptable salts thereof.
In a further aspect of the present invention, the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
The compounds according to the invention may have at least one asymmetric centre, and may exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, wafers, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insuffilation. Oral compositions such as tablets, pills, capsules or wafers, are particularly preferred.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include those comprising a compound of formula (I), as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The present invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises bringing a compound of formula (I) into association with a pharmaceutically acceptable carrier or excipient.
The compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity.
Thus, for example, an excess of tachykinin, and in particular substance P, activity is implicated in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; delerium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer""s disease, senile dementia, dementia of the Alzheimer""s type, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson""s disease, Huntington""s disease, Pick""s disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson""s disease and other extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour; substance-related disorders arising from the use of alcohol, amphetamines (or amphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, intoxication, withdrawal, intoxication delerium, withdrawal delerium, persisting dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders; epilepsy; Down""s syndrome; demyelinating diseases such as MS and ALS and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid haemorrhage or cerebral oedema.
Tachykinin, and in particular substance P, activity is also involved in nociception and pain. The compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pain predominates, including soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, episiotomy pain, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low back pain; sciatica; ankylosing spondylitis, gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, bronchospasm and cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; ophthalmic conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganglioblastomas and small cell carcinomas such as small cell lung cancer.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, Crohn""s disease, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo, dizziness and Meniere""s disease, surgery, migraine, variations in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; plasma extravasation resulting from cytokine chemotherapy, disorders of bladder function such as cystitis, bladder detrusor hyper-reflexia and incontinence; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, vascular headache, migraine and Reynaud""s disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine.
The compounds of formula (I) are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting.
The compounds of formula (I) are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula (I) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy, and emesis induced by other pharmacological agents, for example, rolipram.
Examples of such chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.
Particular examples of chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and Vomiting: Recent Research and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Fla., USA (1991) pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al in Cancer Treatment Reports (1984) 68(1), 163-172].
The compounds of formula (I) are also of use in the treatment of emesis induced by radiation including radiation therapy such as in the treatment of cancer, or radiation sickness; and in the treatment of post-operative nausea and vomiting.
It will be appreciated that the compounds of formula (I) may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate or sequential use for the relief of emesis. Such combined preparations may be, for example, in the form of a twin pack.
A further aspect of the present invention comprises the compounds of formula (I) in combination with a 5-HT3 antagonist, such as ondansetron, granisetron or tropisetron, or other anti-emetic medicaments, for example, a dopamine antagonist such as metoclopramide or domperidone or GABAB receptor agonists such as baclofen. Additionally, a compound of formula (I), either alone or in combination with one or more other anti-emetic therapeutic agents, may be administered in combination with an anti-inflammatory corticosteroid, such as dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, flunisolide, budesonide, or others such as those disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712. Dexamethasone (Decadron(trademark)) is particularly preferred. Furthermore, a compound of formula (I) may be administered in combination with a chemotherapeutic agent such as an alkylating agent, antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as described above. In general, the currently available dosage forms of the known therapeutic agents for use in such combinations will be suitable.
Suitable methods for determining the anti-emetic effects of compounds of the present invention are well known in the art, for example, using the ferret model of cisplatin-induced emesis described by F. D. Tattersall et al, in Eur. J. Pharmacol., (1993) 250, R5-R6.
The compounds of formula (I) are also particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain.
The compounds of formula (I) are also particularly useful in the treatment of depression including depressive disorders, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or depression.
The present invention further provides a compound of formula (I) for use in therapy.
According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.
The present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I).
According to a further aspect of the present invention, it may be desirable to treat any of the aforementioned conditions with a combination of a compound according to the present invention and one or more other pharmacologically active agents suitable for the treatment of the specific condition. The compound of formula (I) and the other pharmacologically active agent(s) may be administered to a patient simultaneously, sequentially or in combination.
Thus, for example, for the treatment of respiratory diseases such as asthma, a compound of formula (I) may be used in conjunction with a bronchodilator, such as a xcex22-adrenergic receptor agonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula (I) and the bronchodilator may be administered to a patient simultaneously, sequentially or in combination.
Likewise, a compound of the present invention may be employed with a leukotriene antagonists, such as a leukotriene D4 antagonist such as a compound selected from those disclosed in European patent specification nos. 0 480 717 and 0 604 114 and in U.S. Pat. Nos. 4,859,692 and 5,270,324. This combination is particularly useful in the treatment of respiratory diseases such as asthma, chronic bronchitis and cough.
The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) and an effective amount of a bronchodilator.
The present invention also provides a composition comprising a compound of formula (I), a bronchodilator, and a pharmaceutically acceptable carrier.
It will be appreciated that for the treatment or prevention of migraine, a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5-HT1 agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
Likewise, for the treatment of behavioural hyperalgesia, a compound of the present invention may be used in conjunction with an antagonist of N-methyl D-aspartate (NMDA), such as dizocilpine.
For the treatment or prevention of inflammatory conditions in the lower urinary tract, especially cystitis, a compound of the present invention may be used in conjunction with an anti-inflammatory agent such as a bradykinin receptor antagonist.
The present invention also provides a composition comprising a compound of formula (I), a bronchodilator, and a pharmaceutically acceptable carrier.
It will be appreciated that for the treatment or prevention of pain or nociception, a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs and, in particular, opioid analgesics, especially morphine. Specific anti-inflammatory agents include diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam and sulindac. Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of pain or nociception.
It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents.
Suitable classes of anti-depressant agent include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, (xcex1-adrenoreceptor antagonists and atypical anti-depressants.
Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof. Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.
Suitable selective serotonin reuptake inhibitors include: fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof.
Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof.
Suitable reversible inhibitors of monoamine oxidase include: moclobemide, and pharmaceutically acceptable salts thereof.
Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venlafaxine, and pharmaceutically acceptable salts thereof.
Suitable CRF antagonists include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.
Suitable atypical anti-depressants include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof.
Suitable classes of anti-anxiety agent include benzodiazepines and 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists.
Suitable benzodiazepines include: alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereof.
Suitable 5-HT1A receptor agonists or antagonists include, in particular, the 5-HT1A receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an anti-depressant or anti-anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an anti-depressant or anti-anxiety agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of depression and/or anxiety.
It will be appreciated that for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents.
The present invention accordingly provides the use of a compound of formula (I) and an anorectic agent for the manufacture of a medicament for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an anorectic agent, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) and an anorectic agent, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the compound of formula (I) and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of eating disorders. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a compound of formula (I) and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
Suitable anoretic agents of use in combination with a compound of the present invention include, but are not limited to, aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
A particularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
Particularly preferred halogenated amphetamine derivatives of use in combination with a compound of the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.
It will be appreciated that for the treatment or prevention of obesity, the compounds of the present invention may also be used in combination with a selective serotonin reuptake inhibitor (SSRI).
The present invention accordingly provides the use of a compound of formula (I) and an SSRI for the manufacture of a medicament for the treatment or prevention of obesity.
The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an SSRI, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of obesity comprising a compound of formula (I) and an SSRI, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the compound of formula (I) and SSRI may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of obesity. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a compound of formula (I) and an SSRI as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of obesity.
Suitable selective serotonin reuptake inhibitors of use in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof.
As used herein xe2x80x9cobesityxe2x80x9d refers to a condition whereby a mammal has a Body Mass Index (BMI), which is calculated as weight per height squared (kg/m2), of at least 25.9. Conventionally, those persons with normal weight, have a BMI of 19.9 to less than 25.9.
The obesity herein may be due to any cause, whether genetic or environmental. Examples of disorders that may result in obesity or be the cause of obesity include overeating and bulimia, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich""s syndrome, Type II diabetes, GH-deficient subjects, normal variant short stature, Turner""s syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia.
xe2x80x9cTreatmentxe2x80x9d (of obesity) refers to reducing the BMI of the mammal to less than about 25.9, and maintaining that weight for at least 6 months. The treatment suitably results in a reduction in food or calorie intake by the mammal.
xe2x80x9cPreventionxe2x80x9d (of obesity) refers to preventing obesity from occurring if the treatment is administered prior to the onset of the obese condition. Moreover, if treatment is commenced in already obese subjects, such treatment is expected to prevent, or to prevent the progression of, the medical sequelae of obesity, such as, e.g., arteriosclerosis, Type II diabetes, polycycstic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
A further aspect of the present invention comprises the use of a compound of formula (I) for achieving a chronobiologic (circadian rhythm phase-shifting) effect and alleviating circadian rhythm disorders in a mammal. The present invention is further directed to the use of a compound of formula (I) for blocking the phase-shifting effects of light in a mammal.
The present invention further relates to the use of a compound of formula (I) for enhancing or improving sleep quality, in particular by increasing sleep efficiency and augmenting sleep maintenance, as well as for preventing and treating sleep disorders and sleep disturbances, in a mammal.
In a preferred embodiment, the present invention provides a method for the phase advance or phase delay in the circadian rhythm of a subject which comprises administering to the subject an appropriate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of emesis, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of psychiatric disorders, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
Compounds of formula (I) wherein X=O may be prepared by coupling of a carboxylic acid 1 with a cyclic amine 2: 
where Het, Y, Z and R4 have the same meanings as before. The coupling may be effected using any of the coupling agents commonly used for promoting amide bond formation, such as carbonyldiimidazole (CDI) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in combination with 1-hydroxybenzotriazole hydrate (HOBT). The reaction generally takes place at ambient temperature in an aprotic solvent in the presence of base.
Compounds of formula (I) wherein X=S may be prepared by treatment of the corresponding compounds wherein X=O with Lawesson""s reagent. Likewise, compounds of formula (I) wherein X=two hydrogens may be obtained by reduction of the corresponding compounds wherein X=O, e.g. using borane/tetrahydrofuran complex. Alternatively, the compounds of formula (I) wherein X=two hydrogens may be obtained by reductive alkylation of the amines 2 by the aldehydes 3:
Hetxe2x80x94Yxe2x80x94CHO xe2x80x83xe2x80x833 
where Het and Y have the same meanings as before. The reaction is conveniently effected in dichloroethane solution in the presence of sodium triacetoxyborohydride and glacial acetic acid. The aldehydes 3 are obtainable by reduction of the alkyl esters of the carboxylic acids 1, e.g. using diisobutylaluminium hydride in an inert solvent.
When Het represents heterocyclic residue (a), the acids 1 may be obtained by reaction of the iodopyridinamines 4 with the alkynes 5, followed by hydrolysis of the methyl ester group: 
where A, R1a, R1b, Y and R3 have the same meanings as before. The reaction may be carried out at 100xc2x0 C. in DMF in the presence of palladium (II) acetate, triphenylphosphine, lithium chloride and sodium carbonate.
When Het represents heterocyclic residue (b) in which the optional double bond indicated by the dotted line is present, the acids 1 may be obtained by alkylation of the indole derivatives 6 with the esters 7, followed by hydrolysis of the ester group: 
Halxe2x80x94Yxe2x80x94CO2R xe2x80x83xe2x80x837 
where Hal represents a leaving group such as halogen, especially chlorine or bromine, R represents an alkyl group, such as methyl or ethyl, and B, R1a, R1b, Y and R3 have the same meanings as before. Alternatively, the indoles 6 may undergo Michael addition to methyl or ethyl acrylate, followed by hydrolysis of the ester function, to provide acids 1 in which Y represents xe2x80x94CH2CH2xe2x80x94. The addition reaction may be carried out at moderately elevated temperatures in the presence of a base such as potassium carbonate.
The indoles 6 may be prepared by coupling of an iodoamine 8 with an alkyne R3xe2x80x94Cxe2x89xa1CH to form the adduct 9, which is subsequently cyclised to 6: 
where B, R1a, R1b and R3 have the same meanings as before. The coupling takes place in the presence of a Pd(0) catalyst, cuprous iodide and diethylamine, and the cyclisation of 9 may be effected by heating at 120xc2x0 C. in DMF solution in the presence of calcium carbonate and cuprous iodide.
Alternatively, an amine 10 may be reacted with R3xe2x80x94COCl to form the amide 11, which is subsequently cyclised to 6: 
where B, R1a, R1b and R3 have the same meanings as before. The cyclisation of 11 to 6 may be effected by treatment with butyllithium in THF.
When Het represents heterocyclic residue (c), the acids 1 may be prepared from the aldehydes 12 which are in turn available from the azaindoles 13 by reaction with N-(chloromethylene)-N-methylmethanaminium chloride: 
where R1a, R1b and R3 have the same meanings as before. The azaindoles 13 may be prepared by reaction of the appropriate 2-aminopyridines with R3xe2x80x94COCH2Br in the presence of base. Reaction of aldehydes 12 with ethyl (diethoxyphosphinyl)acetate, or with a suitable Wittig reagent, in the presence of strong base provides the ethyl esters of the acids 1 in which Het represents (c) and Y represents xe2x80x94CHxe2x95x90CHxe2x80x94.
When Het represents heterocyclic residue (d), the acids 1 may be prepared from the imidazoles 14 by N-alkylation with 7 or Michael addition to methyl or ethyl acrylate, by the methods described previously for the indoles 6. The imidazoles 14 are available by reaction of the diamines 15 with R3xe2x80x94COCl: 
where B, R1a, R1b and R3 have the same meanings as before. The first step of the reaction is carried out at ambient temperature or below in a solvent such as dichloromethane in the presence of a tertiary amine, and then the initially-formed anilide is heated with acetic acid at about 100xc2x0 C. to effect cyclisation to 14.
When Het represents heterocyclic residue (e), the acids 1 may be prepared by reduction of the indole derivatives 16: 
where B, Y, R1a, R1b and R3 have the same meanings as before. The reduction may be effected by any of the conventional methods, e.g. by treatment with sodium cyanoborohydride in trifluoroacetic acid. In an alternative (and preferred) synthesis sequence, the reduction of the indole ring is carried out subsequent to the coupling of acid 16 with amine 2. The indoles 16 are available by reaction of arylhydrazines 17 with ketones 18: 
where B, Y, R1a, R1b and R3 have the same meanings as before. The reagents are allowed to react at ambient temperature in ethanol to form an adduct which is subsequently refluxed in trifluoroacetic acid to complete the cyclisation.
In an alternative route to the compounds of formula (I) wherein Y represents xe2x80x94CH2CH2xe2x80x94, X is O, and Het represents heterocyclic residues (b) or (d), indoles 6 or imidazoles 14 are reacted with propenamides 19: 
where Z and R4 have the same meanings as before. The addition reaction may be carried out in DMF solution at about 100xc2x0 C. in the presence of a base such as potassium carbonate.
Where they are not commercially available, the starting materials 2, 4, 5, 7, 8, 10, 15, 17, 18, 19, R3xe2x80x94Cxe2x89xa1CH, R3COCl and R3COCH2Br may be prepared by the methods described in the worked examples provided herein, or by other standard methods known to those skilled in the art.
It will be appreciated that a particular compound in accordance with formula (I) may be converted to a different compound, also in accordance with formula (I), by standard synthetic procedures. For example, compounds of formula (I) in which Het represents (a) or (e) and R2 is H may be converted to the corresponding compounds in which R2 is other than H by conventional methods of N-alkylation or acylation. (Alternatively, such procedures can be carried out on the synthetic precursors of the relevant compounds of formula (I)).
Similarly, a compound of formula (I) wherein Het represents (b) and the optional double bond represented by the dotted line is present may be reduced to the corresponding 2,3-dihydroindole (in which the aforesaid double bond is absent) by standard methods, such as treatment with sodium cyanoborohydride in trifluoroacetic acid.
As a further example of this protocol, compounds of formula (I) in which Y represents a linear alkylene chain may be alkylated at the carbon atom of Y adjacent to the carbonyl group, thereby providing the corresponding compounds of formula (I) wherein Y represents a branched alkylene chain. Any of the normal techniques of C-alkylation may be used, such as treatment with sodium hydride and the appropriate alkyl halide.
Similarly, compounds of formula (I) wherein Y represents xe2x80x94CHxe2x95x90CHxe2x80x94 may be converted to the corresponding compounds in which Y represents xe2x80x94CH2CH2xe2x80x94. The reduction may be effected by any of the standard techniques, such as treatment with sodium borohydride in pyridine solution.
The compounds of formula (I) prepared according to the methods described above may be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography or a combination thereof.
Although the reaction schemes described herein are reasonably general, it will be understood by those skilled in the art of organic synthesis that one or more functional groups present in a given compound of formula (I) may render the molecule incompatible with a particular synthetic sequence.
In such a case an alternative route, an altered order of steps, or a strategy of protection and deprotection may be employed. In all cases the particular reaction conditions, including reagents, solvent, temperature, and time, should be chosen so that they are consistent with the nature of the functionality present in the molecule.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01165. The compounds were found to be active with IC50 at the NK1 receptor of less than 100 nM on said test method.
The following non-limiting Examples serve to illustrate the preparation of compounds of the present invention: